Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis
Authors: Paul Diefenhardt, Marie Braumann, Thomas Schömig, Bastian Trinsch, Claudio Sierra Gonzalez, Janine Becker-Gotot, Linus A. Völker, Lioba Ester, Amrei M. Mandel, Daniel Hawiger, Ali T. Abdallah, Bernhard Schermer, Heike Göbel, Paul Brinkkötter, Christian Kurts, Thomas Benzing, Sebastian Brähler
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Treatment of acute, crescentic glomerulonephritis (GN) consists of unspecific and potentially toxic immunosuppression. T cells are central in the pathogenesis of GN, and various checkpoint molecules control their activation. The immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown potential for restraining inflammation in other T-cell–mediated disease models. To investigate its role in GN in a murine model of crescentic nephritis, the authors induced nephrotoxic nephritis in BTLA-deficient mice and wild-type mice. They found that BTLA has a renoprotective role through suppression of local Th1-driven inflammation and expansion of T regulatory cells and that administration of an agonistic anti-BTLA antibody attenuated experimental GN. These findings suggest that antibody-based modulation of BTLA may represent a treatment strategy in human glomerular disease. Background Modulating T-lymphocytes represents a promising targeted therapeutic option for glomerulonephritis (GN) because these cells mediate damage in various experimental and human GN types. The immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown its potential to restrain inflammation in other T-cell–mediated disease models. Its role in GN, however, has not been investigated. Methods We induced nephrotoxic nephritis (NTN), a mouse model of crescentic GN, in Btla -deficient ( Btla KO ) mice and wild-type littermate controls and assessed disease severity using functional and histologic parameters at different time points after disease induction. Immunologic changes were comprehensively evaluated by flow cytometry, RNA sequencing, and in vitro assays for dendritic cell and T-cell function. Transfer experiments into Rag1 KO mice confirmed the observed in vitro findings. In addition, we evaluated the potential of an agonistic anti-BTLA antibody to treat NTN in vivo . Results The Btla KO mice developed aggravated NTN, driven by an increase of infiltrating renal Th1 cells. Single-cell RNA sequencing showed increased renal T-cell activation and positive regulation of the immune response. Although BTLA-deficient regulatory T cells (Tregs) exhibited preserved suppressive function in vitro and in vivo , Btla KO T effector cells evaded Treg suppression. Administration of an agonistic anti-BTLA antibody robustly attenuated NTN by suppressing nephritogenic T effector cells and promoting Treg expansion. Conclusions In a model of crescentic GN, BTLA signaling effectively restrained nephritogenic Th1 cells and promoted regulatory T cells. Suppression of T-cell–mediated inflammation by BTLA stimulation may prove relevant for a broad range of conditions involving acute GN.